Multiple sclerosis (MS) is a common autoimmune demyelinating disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. The most compelling and consistently replicated evidence for an MS susceptibility gene has been found at the major histocompatibility complex (MHC) superlocus on chromosome 6p21.3. However, the exact gene or genes and mechanisms by which the MHC affects MS are still undefined. Our overall objective is to characterize the complete repertoire of MHC genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of the rapid progress in delineating the landscape of genetic organization and variation across the human genome. In specific aim 1 we describe a high density association analysis of the causal variation(s) within the 4 MB MHC locus. Over 1500 validated SNPs will be genotyped in 1,000 MS trios. Family-based association testing for alleles, haplotypes and genotypes in each block will be performed using transmission disequilibrium testing methods. In specific aim 2, discrete segments of interest identified in specific aim 1 will be followed-up with additional association mapping using additional SNP markers in the original and confirmatory datasets. MS susceptibility genes located within blocks of interest will then be identified by direct sequencing. In the third aim, we will address the issue of genetic modifiers in the MHC region focusing first on the underlying causes of primary progressive MS. Clinical and laboratory data such as age and site of disease onset, disability at entry of study (EDSS), lesion distribution, and progression will be also incorporated into the analysis of genomic data to directly address the question of heterogeneity in MS by analysis of the correlation between different phenotypes and genotypes.